1. a transition from disease to health brain integration 3...

1. A Transition From Disease to Health 2. Heart – Brain Integration 3. Imaging / Omics / Regeneration / Life Style Complex CAD (5) PVD-P Valv. – CM AF Sub-Clinical Arterial (2) DBD/Frailty (4) Health Political (1) Personal (3)

Global – From Patient to Population (3)

1980 1990 2000 2010 2015

1990 2000 2010 2015 2020

Cortical Atrophy (Alzheimer’s),

White Matter & Lacunar Lesions (DBD)

JC Kovacic, V Fuster et. al. Circulation. 2011;123:1900

MA Lim et. al. Clin Geriatr Med. 2009;25:191.

Projected US Population Demographics by Age / Sex

2010, 2030, and 2050

JC Kovacic, EG Nabel, V Fuster et.al. Circ. 2011;123:1650 US Census Bureau

In 2030, nearly 1 in 5 US residents is expected to by > 65 years.

By 2050, this age group is projected to more than double

2010

2030

2050

Projected Number of Americans 65 Years of

Age or Older with Alzheimer’s Disease

S Okie NEJM. 2011;365:1069

1. A Transition From Disease to Health 2. Heart – Brain Integration 3. Imaging / Omics / Regeneration / Life Style Complex CAD (5) PVD-P Valv. – CM AF Sub-Clinical Arterial (2) DBD/Frailty (1/4) Health Political (1) Personal (3)


1980 1990 2000 2010 2015

1990 2000 2010 2015 2020

CT Loy et. al. Lancet 2014; 383: 828 (Australia)

1). DBD / AD - Mendelian vs Acquired

25% >65y – FH Dementia, 20% Dementia

DBD/AD - CVRFs, Lacunar Les., < Cognitive

MRI – Perfusion

1.V Novak, I Hajjar. Nat. Rev. Cardiol. 2010;7:686(HMS) 2. HW Querfurth, FM LaFerla. NEJM 2010; 362:329 Ischemia affects 60 to 90% of patients with Alzheimer’s – RFs ? 3. WB White et al.Circ 2011;124:2312 (Farmington,Yale) 4. AHA/ASA, Stroke 2011; 42:2672 5. WHO - Dementia report 2012 6. JB Toledo et al. Brain July 10, 2013 – Autopsy (n=6000) 7. C Russo, RL Sacco et.al. Circ. 2013;128:1105 8. JR Kizer Circ 2013;128:1045 9. CARDIA (K Yaffe et al) Circ. 2014; 129 (In Press) 10. JI Friedman, ZA Fayad, J Narula, V Fuster - 2014 (In Press) 11. N Mattsson et al. Brain 2014;137:150

ALZHEIMER’S - VASCULAR COMPONENT - RFs ?

JC Kovacic, V Fuster et. al. Circulation. 2011;123:1900

MA Lim et. al. Clin Geriatr Med. 2009;25:191.

DBD/AD - CVRFs, Lacunar Les., < Cognitive

MRI – Perfusion

1.V Novak, I Hajjar. Nat. Rev. Cardiol. 2010;7:686(HMS) 2. HW Querfurth, FM LaFerla. NEJM 2010; 362:329 Ischemia affects 60 to 90% of patients with Alzheimer’s – RFs ? 3. WB White et al.Circ 2011;124:2312 (Farmington,Yale) 4. AHA/ASA, Stroke 2011; 42:2672 5. WHO - Dementia report 2012 6. JB Toledo et al. Brain July 10, 2013 – Autopsy (n=6000) 7. C Russo, RL Sacco et.al. Circ. 2013;128:1105 8. JR Kizer Circ 2013;128:1045 9. CARDIA (K Yaffe et al) Circ. 2014; 129 (In Press) 10. JI Friedman, ZA Fayad, J Narula, V Fuster - 2014 (In Press) 11. N Mattsson et al. Brain 2014;137:150

Early Adult to Midlife

CV Risk Factors & Cognitive Function

Studies have linked midlife and late-life CV risk factors

(CVRFs) to cognitive function, yet little is known about

CVRF exposure in early adulthood and subsequent

cognitive function. In a prospective study of 3381 adults

(age, 18-30 years at baseline) with 25 years of follow-up, we

assessed cognitive function at year 25 (2010-2011) with the

Digit Symbol Substitution Test, Stroop Test, and Rey

Auditory Verbal Learning Test. Cumulative exposure to

CVRFs from early to middle adulthood was associated with

worse cognition in midlife.

CARDIA (K Yaffe, et al.) Circulation 2014; 129 (In Press) – 4 Cities

Early Adult to Midlife (N=3381, FU 25 yrs)

CV Risk Factors and Cognitive Function

CARDIA (K Yaffe, et al.) Circ 2014 (Birmingham, Chicago, Minneapolis, Oakland)

JI Friedman, ZA Fayad, J Narula, V Fuster - 2014 (In Press) – MRI: WMH, BF – BP, Diabetes

Adjusted For Age, Sex, Race And Education

Neuroimaging (MRI arterial and structural, PET Florbetapir) was tested in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer’s disease (n = 24). Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-b load was related to lower cerebral blood flow

Circulation. 2014;130:786

TAN SNIP Projects

TRANS-ATLANTIC NETWORK TO STUDY STEPWISE NONINVASIVE

IMAGING AS A TOOL FOR CV PROGNOSIS & PREVENTION



1980 1990 2000 2010 2015

1990 2000 2010 2015 2020

2). Silent Cerebral Infarcts

Cardiac Disease And Procedures

ME Hassell et. al. Nat. Rev. Cardiol. 2013;10:696

2a). LA Reservoir Function (3D Echo) and Volumes Are Associated With Subclinical CVD (MRI)

CABL Study (C Russo et. al.) J Am Coll Cardiol Img 2013;6:313 (US. Japan)

Normal Brain And Subclinical Ischemic Changes

White Matter Hyperintensities

Cortical infarction Lacunar infarction

Prevalence of Silent Cerebral Ischemia in Paroxysmal and Persistent AF and Correlation With Cognitive Function

F Gaita et. al. J Am Coll Cardiol 2013;62:1990 (Italy)

Prevalence Of Scis In Patients With AF According To The Method Of SCI Diagnosis

S Kalantarian et. al. Ann Intern Med. 2014;161:650

Cardiac Imaging For Assessment Of Left Atrial Appendage Stasis & Thrombosis

J Romero et. al. Nat Rev Cardiol. 2014;11:470

JP Fanning et. al. Circulation. 2014;129:504

2b). Spectrum Of Neurological Injury In TAVI


Thirty-day Stroke Incidence Following TAVI


Silent cerebral ischemic lesions on DW-MRI post-TAVI


TAVI -Transcranial Doppler Detected Embolic Load


Tavi -Embolic Protection Devices

Embrella Deflector (Edwards LifeSciences,

Irvine, CA)

Montage 2 Capture Device (Claret Medical, Santa Rosa,

CA)

Triguard Cerebral Deflector

(Keystone Heart, Herzliya, Israel)



1980 1990 2000 2010 2015

1990 2000 2010 2015 2020

3). Frailty: The Hallmarks of Aging Non-specific Extreme fatigue, unexplained weight loss, frequent infections. Falls So-called hot fall is related to a minor illness that reduces postural

balance below a crucial threshold necessary to maintain gait integrity. Spontaneous falls occur in more severe frailty.

Delirium Rapid onset of fluctuating confusion and impaired awareness. Delirium

is related to reduced integrity of brain function and is independently associated with adverse outcomes.

Fluctuating disability Fluctuating disability is day-to-day instability.

A Clegg et al., Lancet 2013; 381:752

J Afilalo et. al. JACC 2014;63:747 (Quebec, NY, Boston, NC)

Aging / Frailty

Oxidative Stress on Telomere

B Niemann et. al. JACC 2011; 57: 577. R Madonna, R De Caterina et. al EHJ 2011;32:1190 (Houston &Chieti, Italy) JC Kovacic, EG Nabel, V Fuster – Circ. 2011;123:1650

1

2

4

3

Cell/Molecular Pathways & Aging

CB Newgard et. al. J Clin Invest. 2013;123:946

Oxidative Stress & Telomere Attrition

C Lopez-Otin et. al. Cell. 2013;153:1194 – CV RFs…. F Fyhrquist et al., Nat Rev Cardiol 2013; 10:274 – CV RFs….

Senescence Assoc. Secret. Phenotype (SASP)

Chronic Diseases And Disabilities

T Tchkonia et. al. J Clin Invest. 2013;123:966

J Afilalo et. al. JACC 2014;63:747 (Quebec, NY, Boston, NC)

Oxidative Stress & Environment

F Fyhrquist et al. Nat Rev Card. 2013; 10:274

PESA (V Andres, V Fuster et al) 2015

Telomere Attrition & Shortening •Smoking •Obesity •Sedentary lifestyle •Mental stress / Depression Inhibition Of Telomere Shortening •Healthy lifestyle

Recent Studies - Dementia Epidemic

Study Data Source Factors Manton et al. National long-term care Higher educational level, (United States) survey interviews, decline in stroke 1982-1999 incidence Langa et al. Ongoing population-based Higher educational level; (United States) survey of people 51 yr combination of medical, of age lifestyle, demographic, and social factors Schrijvers et al. Population-based cohort Higher educational level, re- (Rotterdam) 55 yr of age in 1990, duction in vascular risk, extended in 2000 decline in stroke incidence Qiu et al. Cross-sectional survey of Favorable changes in risk (Stockholm) people 75 yr of age, factors, especially 1987-1989 and 2001- vascular risk; healthier 2004 lifestyles Matthews et al. Survey interviews of people Higher educational level, (England) 65 yr of age, 1989- better prevention of 1994 (in CFAS I) and vascular disease 2008-2011 (in CFAS II)

EB Larson et al., NEJM 2013; 369:2275

BDI indicates Beck Depression Inventory

Exercise for Depression

G Cooney et. al. JAMA 2014;311:2432 – Borderline under strict criteria

Induction of Mitohormesis Antioxidant Compensation to ROS

JK Liao Eur Heart J. 2012; 33: 1299

J Bouitbir et. al. 2012; 33: 1397

Sirtuins (SIRT) - Targets for Deacetylation Suppress Reactive Oxygen Species on Mitochondria.

L Guarente N Engl J Med 2011;364:2235

J Couzin-Frankel Science 2011;334:1194

John O’Keefe May-Britt Moser Edvard Moser

A. Petherick. Lancet 2014;384:1333

TAN SNIP Projects

TRANS-ATLANTIC NETWORK TO STUDY STEPWISE NONINVASIVE

IMAGING AS A TOOL FOR CV PROGNOSIS & PREVENTION

A

Health / Behavior

Science, Health, Education (SHE)

2 . C

B

Marketing / IIIP Group / PPPI

“Extended healthy lives” in part due to medical research

generates dramatic returns - Albert & Mary Lasker Found.- 2002



1980 1990 2000 2010 2015

1990 2000 2010 2015 2020

4) MEETING TARGETS FOR RISK FACTOR CONTROL?

Risk Factors - Proportion of Participants at Goal % – 1 year

Trials LDL SBP DBP Hb A1C Meet Goals

Base FU

BARI-2D 75 56 70 52 14 20

COURAGE 51 55 55 59 12 19

FREEDOM 55 63 53 55 12 20

Freedom, Bari-2D, Courage Investigators, JACC 2013;61:1607 PURE (S Yusuf et al.) Lancet 2011; Aug 28 - Poor Countries,7% !!! NHANES, AHA, NHLBI-JNC-7, NHLBI-NCEP P Muntner, V Fuster et al., AHJ 2011; 161: 719 – 49 seconds !!!!

CNIC-F*-FERRER POLYPILL, 2ary PREVENTION.

Am. H J 2011;162:811

Semin.Thor.Cardiov.Surg 2011;23:24

JACC, 2014-In Press - Approved in 22 Countries

* Fuster - Funding: European Community

FOOD INTERACTION

PHARMACOKINETIC INTERACTION WITH ASPIRIN

PHARMACOKINETIC INTERACTION WITH

SYMVASTATIN

PHARMACOKINETIC INTERACTION WITH RAMIPRIL

PHARMACODYNAMIC INTERACTION WITH ASPIRIN

PHARMACODYNAMIC INTERACTION WITH

SYMVASTATIN

PHARMACODINAMIC INTERACTION WITH RAMIPRIL

BIO-EQUIVALENCE

ASA, Statin, ACE-Inhibitor

Argentina Brazil Paraguay Italy Spain

FOCUS 1 & 2

FREEDOM

AETNA

EU 2020

1. A Transition From Disease to Health 2. Heart – Brain Integration 3. Imaging / Omics / Regeneration / Life Style Complex CAD (5) PVD-P Valv. – CM AF Sub-Clinical Arterial (2) DBD/Frailty (4) Health Political (1) Personal (3)


1980 1990 2000 2010 2015

1990 2000 2010 2015 2020

1. a transition from disease to health brain integration 3...

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